Abstract. Staphylococcus aureus is a Gram-positive bacterium that is clinically prominent with new isolates emerging that exhibit drug resistance, making treatments challenging with the current drug arsenal. S. aureus is the most commonly recognized multi-drug resistant (MDR) pathogen and it often referred to as a ?superbug?, methicillin resistant S. aureus (MRSA) being the most prominent. MRSA is no longer limited to medical hospitals and are rapidly transmitted from person to person. With the growing problem, there is concern about effective treatment, leading to a fervent need for new antimicrobials. Using Caenorhabditis elegans as an infection model, we performed a high throughput screen (HTS) to identify compounds with activity against S. aureus, particularly MRSA. Our investigation determined that the anti- inflammatory compound auranofin (an FDA approved drug) and the medicinal herb extract shikonin are able to improve survival of infected nematodes, exhibiting minimal inhibitory concentrations at 0.25 ?g/ml and 4 ?g/ml, respectively. To accommodate our investigations of auranofin and shikonin as potential new antimicrobial compounds against S. aureus, we will interrogate the molecular target of auranofin, examining the effects to the thioredoxin system, an essential antioxidant defense in many Gram-positive bacteria. Our examination will include a survey of clinical isolates and low dose exposure to these compounds to determine if bacteria have available resistance mechanisms or can develop resistance (aim 1). Our aim is to investigate the translation of TrxR targeted compounds to mammalian systems using mice as an infection model for S. aureus. We will determine the drug efficacy of our TrxR targeted compounds on S. aureus inhibition, evaluating systemic and local infections (aim 2). Further, to build a new class of thioredoxin system inhibitory antibiotics, we will engage an antibatcerial target specific screen to identify new compounds, enhancing our chances of finding a drugable compound (aim 3). Thus driving the investigation of auranofin, shikonin, and other TrxR inhibitory compounds toward use as a treatment option for specific bacterial infections.